Alzheimer's disease (AD) is characterized by progressive memory impairment and cognitive decline. Its hallmark pathological lesions are amyloid deposits (senile plaques), neurofibrillary tangles and neuronal loss in specific brain regions. The amyloid deposits are composed of amyloid beta peptides (Aβ) of 40 to 43 amino acid residues, which are the proteolytic products of the amyloid precursor protein (APP). Neurofibrillary tangles are the intracellular filamentous aggregates of hyperphosphorylated tau proteins (Selkoe, Science, 275: 630-631, 1997).
The pathogenesis of AD has not been fully understood, but it is expected to be a multi-factored event. Accumulation and aggregation of Aβ in brain tissue is believed to play a pivotal role in the disease process, also know as the amyloid cascade hypothesis (Golde, Brain Pathol., 15: 84-87, 1995). According to this hypothesis, Aβ, particularly Aβ42, is prone to form various forms of aggregates, ranging from small oligomers to large, elongated profibrile structures. These aggregates are neurotoxic and are responsible for the synaptic pathology associated with the memory loss and cognition decline in the early stage of the disease (Klein et al., Neurobiol. Aging, 25: 569-580, 2004). A recent publication suggests that reduction of Aβ in a triple transgenic mouse model also prevents intracellular tau deposition (Oddo et al., Proc. Neuron, 43:321-332, 2004). This finding suggests that the extracellular amyloid deposition may be causative for subsequent neurofibrillary tangle formation, which may in turn lead to neuronal loss.
Immunization of APP transgenic mice with Aβ antigen can reduce the brain Aβ deposits and mitigate disease progression. This was first reported by Shenk et al., Nature, 400: 173-177, 1999, and has now been corroborated by a large number of studies involving different transgenic animal models, various active vaccines as well as passive immunization with Aβ specific monoclonal antibodies (Bard et al., Nature Med, 6: 916-919, 2000; Janus et al., Nature, 408: 979-982, 2000; Morgan et al., Nature, 408: 982-985, 2000; DeMattos et al., Proc. Natl. Acad. Sci., 98: 8850-8855, 2001; Bacskai et al., J. Neurosci., 22: 7873-7878, 2002; Wilcock et al., J. Neurosci., 23: 3745-3751, 2003). Consistent with these animal data, three published evaluations of postmortem human brain tissues from patients who had previously received active immunization with a pre-aggregated Aβ (1-42) immunogen (AN1792, Betabloc) showed regional clearance of senile plaques (Nicoll et al., Nature Med., 9: 448-452, 2003; Ferrer et al., Brain Pathol., 14: 11-20, 2004; Masliah et al., Neurology, 64: 129-131, 2005). This data collectively indicates that vaccines that effectively elicit antibody responses to Aβ antigens are efficacious against the pathological senile plaques found in AD. However, the mechanism of vaccine or antibody efficacy remains to be defined.
The most advanced immunotherapy-based AD program in the public domain had been an active immunization Phase II vaccine trial using AN1792 (Betabloc), a vaccine composed of pre-aggregated Aβ (1-42) co-administered with the adjuvant, QS-21™ (Antigenics, New York, N.Y.). In January 2002, this study was terminated when four patients showed symptoms consistent with meningoencephalitis (Senior, Lancet Neurol., 1: 3, 2002). Ultimately, 18 of 298 treated patients developed signs of meningoencephalitis (Orgogozo et al., Neurology, 61: 46-54, 2003). There was no correlation between encephalitis and antibody titer and it has been reported that the likely causative mechanism for this effect was activation of T-cells to the self-immunogen, particularly the mid- and carboxy-terminal portion of the Aβ42 peptide (Monsonego et al., J. Clin. Invest., 112: 415-422, 2003). In support of this conclusion, postmortem examination of brain tissues from two vaccine recipients that developed encephalitis revealed substantial meningeal infiltration of CD4+ T cells in one patient (Nicoll et al., Nature Med., 9: 448-452, 2003) and CD4+, CD8+, CD3+, CD5+, CD7+ T cells in the other (Ferrer et al., Brain Pathol., 14: 11-20, 2004).
Current evidence suggests that increases in plasma Aβ levels following passive or active immunization reflect the initiation of a peripheral sink as a precursor to subsequent decreases in brain Aβ. The peripheral sink refers to a change in the equilibrium of brain and plasma Aβ stores resulting in a net efflux of central Aβ to the periphery (see, for example, Deane et al., J. Neurosci., 25: 11495-11503, 2005; DeMattos et al., Pro. Natl. Acad. Sci. USA, 98: 8931-8932, 2001). Other studies suggest that this increase in plasma Aβ observed following anti-Aβ immunotherapy is necessary for subsequent decreases in central Aβ to be realized (Cribbs et al., 7th International Conference on AD/PD, Sorrento, Italy, 2005). Thus, when two amino acids within Aβ are substituted (for example, such as occurs with the Dutch and Iowa mutations) the peptide is no longer able to cross from central to peripheral compartments (Davis et al., Neurobiol. Aging, in press, available on line 18 Aug. 2005). When mice expressing this mutant form of Aβ and the Swedish mutation were immunized, no elevations in plasma Aβ were found and no subsequent lowering of brain Aβ was noted. By contrast, mice expressing the wild-type human Aβ sequence plus the Swedish mutation responded to active immunization with both increases in plasma Aβ and subsequent decreases in central Aβ (Cribbs et al., 7th International Conference on AD/PD, Sorrento, Italy, 2005). Accordingly, it is expected that any active vaccine immunogen capable of generating an immune response that results in the elevation of plasma Aβ levels will be useful for the treatment of Alzheimer's disease and related disorders characterized by elevated brain Aβ levels.
Applicants herein have surprisingly found that an antigen which eliminated T-cell epitopes, to avoid a self T-cell response, is immunogenic and elevates plasma Aβ levels. This represents a potential means to produce a safe and effective AD vaccine. Applicants herein provide such an antigen and a formulation for use as an AD vaccine.